This invention relates to a naturally occurring extract Kas from the Melothria Indica Lou plant that inhibits the release of cytokines such as Tumor Necrosis Factor-alpha (TNF-alpha) by immune response cells, such as macrophages, for the therapeutic treatment of disease including sepsis.
Many of the toxic effects of endotoxins can be mimicked in vivo by TNF-alpha or IL-1 beta themselves (Norogrodsky, et. al., 1994, Science 264:1319). Tumor necrosis factor-alpha (TNF-alpha), a 17 Kda protein produced by macrophages and other cells, was discovered by separate groups of investigators pursuing mediators of disparate diseases. The pleiotropic nature of TNF-alpha prevents generalization about whether it is beneficial or injurious. It is clear that, in some instances, the local effects of TNF-alpha improve host defense mechanisms by mobilizing substrate, increasing immune cell function, and stimulating inflammation. But, in other cases, the toxicity of TNF-alpha may cause disease by mediating septic shock, tissue injury, or catabolic illness. TNF-alpha has been implicated in many diseases including: AIDS, Anemia, Autoimmune Disease, Cachexia, Cancer, Cerebral Malaria, Diabetes Mellitus, Disseminated Intravascular Coagulopathy, Eurthyroid Sick Syndrome, Hemorrhagic Shock, Hepatitis, Insulin Resistance, Leprosy, Leukemia, Lymphoma, Meningitis, Multiple Sclerosis, Myocardial Ischemia, Obesity, Rejection Of Transplanted Organs, Rheumatoid Arthritis, Septic Shock, Stroke and Tuberculosis (Tracey, K. J., Tumor Necrosis Factor-alpha in The Cytokine Handbook (Academic Press Limited 1994)).
Septic Shock Syndrome, a frequently lethal complication of infectious disease, kills 85,000-150,000 people in the USA annually (Tracey, K. J., Tumor Necrosis Factor-alpha in The Cytokine Handbook (Academic Press Limited 1994)). This disease is caused by a massive systemic infection by Gram-negative bacteria. Due to excessive stimulation of the host immune system by the endotoxin lipopolysaccharide (LPS), which is present on the outer membrane of the bacteria, the host immune cells, mainly macrophages, produce several cytokines such as Tumor Necrosis Factor-alpha (TNF-alpha), Interleukin 1-Beta (IL-I Beta), Interleukin 6 (IL-6) and Nitric Oxide (NO), which are the main modulators of the response to LPS (Norogrodsky, et. al., 1994, Science 264:1319). It has been reported that anti-TNF monoclonal antibodies prevent the development of septic shock in animal studies (Tracey, et. al., 1987, Nature 330:66; Beutler, 1985, Science 229:869; Mathison, et. al., 1988, J. Clin. Invest. 81:1925; Grau, et. al., 1987, Science 237:1210). These findings provide a rationale for the removal of TNF for the purpose of the treatment of sepsis shock. We have discovered a component designated as Kas from the extract of plant Melothria Indica Lou that functionally removed TNF-alpha by blocking the release of TNF-alpha by macrophage. In a sepsis animal model, we found that Kas prevents death in sepsis-induced mice.
It is the object of this invention to use an extract of the Melothria Indica Lou plant, designated xe2x80x9cKas,xe2x80x9d as a therapeutic agent for the treatment of TNF-related diseases, such as sepsis.
It is another object of this invention to employ a method to isolate and to purify the active component Kas, which is present in the extract of the Melothria Indica Lou plant and inhibits the secretion of TNF by endotoxin-stimulated macrophages.